| First Author | Liu Y | Year | 2021 |
| Journal | Biol Reprod | Volume | 105 |
| Issue | 4 | Pages | 837-845 |
| PubMed ID | 34104947 | Mgi Jnum | J:317268 |
| Mgi Id | MGI:6849543 | Doi | 10.1093/biolre/ioab111 |
| Citation | Liu Y, et al. (2021) A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signaling pathway in mice. Biol Reprod 105(4):837-845 |
| abstractText | Although adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of pregnancies affected by neural tube defects (NTDs), the mechanisms underlying FA-resistant NTDs are poorly understood, and thus NTDs still remain a global public health concern. A high level of Kruppel-like factor 12 (KLF12) exerts deleterious effects on heath in most cases, but evidence for its roles in development has not been published. We observed KLF12-overexpressing mice showed disturbed neural tube development. KLF12-overexpressing fetuses died in utero at approximately 10.5 days post-coitus, with 100% presenting cranial NTDs. Neither FA nor formate promoted normal neural tube closure in mutant fetuses. The RNA-seq results showed that a high level of KLF12 caused NTDs in mice via overactivating the sonic hedgehog (Shh) signaling pathway, leading to the upregulation of patched 1, GLI-Kruppel family member GLI1, hedgehog-interacting protein, etc., whereas FA metabolism-related enzymes did not express differently. PF-5274857, an antagonist of the Shh signaling pathway, significantly promoted dorsolateral hinge point formation and partially rescued the NTDs. The regulatory hierarchy between a high level of KLF12 and FA-resistant NTDs might provide new insights into the diagnosis and treatment of unexplained NTDs in the future. |
